Comparison of vonoprazan dual therapy, quadruple therapy and standard quadruple therapy for Helicobacter pylori infection in Hainan: a single-center, open-label, non-inferiority, randomized controlled trial

Objective To compare the potential efficacy and safety of dual therapy and quadruple therapy with vonoprazan (VPZ) as well as the standard quadruple therapy of proton pump inhibitor (PPI) for the eradication of Helicobacter pylori (Hp) infection in Hainan province. Methods A single-centre, non-blinded, non-inferiority randomized controlled trial was conducted at the outpatient department of gastroenterology at the Second Affiliated Hospital of Hainan Medical University from June 2022 to February 2023. 135 patients aged 18–75 years with Hp infection were enrolled and randomized into three different groups (group V1: VPZ 20 mg twice a day and amoxicillin 1.0 g three times a day for 14 days V2: vonoprazan 20 mg, amoxicillin capsules 1.0 g, furazolidone 0.1 g and bismuth potassiulm citrate 240 mg, twice daily for 14 days;; group V3: ilaprazole 5 mg, Amoxicillin 1.0 g, Furazolidone 100 mg, bismuth potassiulm citrate 240 mg, twice a day for 14 days). Four weeks after the end of treatment, Hp eradication was confirmed by rechecking 13C-urea breath test (UBT). Results The eradication efficacy of V1 and V3 was non-inferior to that of V2, which is consistent with the results obtained from the Kruskal-Wallis H test. The eradication rate by intentional analysis was 84.4% (38/45, 95%CI 73.4%–95.5%, P>0.05) for all the three groups. If analyzed by per-protocol, the eradication rates were 88.4% (38/43, 95%CI 78.4%–98.4%), 92.7% (38/41, 95%CI 84.4%–101.0%),88.4% (38/43，95%CI 78.4%–98.4%) in groups V1, V2 and V3, respectively, which did not show a significant difference (P > 0.05). The incidence of adverse effects was significantly lower in VPZ dual therapy compared to the other two treatment regimens (P < 0.05). VPZ dual therapy or quadruple therapy was also relatively less costly than standard quadruple therapy. Conclusion VPZ dual therapy and quadruple therapy shows promise of not being worse than the standard quadruple therapy by a clinically relevant margin. More studies might be needed to definitively determine if the new therapy is equally effective or even superior. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-024-03225-8.


Introduction
Helicobacter pylori (Hp) is a pathogen that primarily resides in the stomach and infects nearly half of the world's population [1].In China, the prevalence of Hp infection is approximately 40% [2].Most people with Hp infection may not display any obvious gastrointestinal symptoms, or may only show mild indigestion symptoms.However, most infected individuals will have varying degrees of chronic gastritis, and about 15-20% of infected individuals might also develop peptic ulcers and, whereas in more severe cases, gastric cancer or mucosa-associated lymphoid tissue lymphoma [3].According to the 5th National Consensus Report on the Management of Hp Infection in China, Hp eradication therapy has been recommended even for asymptomatic infected patients [4].Hp is classified as a class I carcinogen by World Health Organization's International Agency for Research on Cancer [5] and its eradication can serve as an important strategy to reduce the risk of cancer [6].In China, quadruple therapy (Proton pump inhibitors(PPI) + two kinds of antibiotics + one bismuth agent) is the standard HP eradication treatment regimen [4], which generally has an eradication rate of over 80%, but can exhibit severe shortcomings, such as increasing antibiotic resistance and substantially higher adverse effects [7].In China, Hp resistance to antibiotics such as clarithromycin (CLR), metronidazole and levofloxacin is continuously increasing [8] and is considered as the main reason for the decline in Hp eradication rates [9].
Successful eradication of Hp is associated with suppression of stomach acid in addition to antibiotic sensitivity [10,11].Vonoprazan(VPZ) is a new potassium competitive acid blocker (P-CAB) with strong acid-suppressive effects, which was first approved in Japan in 2015 for the treatment of Hp infection, reflux esophagitis and a range of other gastrointestinal diseases [12].VPZ specifically acts on wall cells to bind to its H+/K+ ATPase transporter protein ions, thereby rapidly preventing K+ ions from entering the proton pump and substantially blocking H+ ions secretion, thus, acting as an acid suppressor [13].VPZ can potentially inhibit 100% of gastric acid for 1 week, the average intragastric pH value can be then maintained at around 6.8, which has a stronger and longer-lasting acid-suppressive effect [14].Eradication regimens with VPZ as an acid-suppressing drug exhibited higher eradication rates than PPI eradication regimens [15][16][17].Therefore, this paper aimed to compare the efficacy and safety of VPZ's dual therapy with VPZ's quadruple therapy as well as standard PPI's therapy for Hp infection eradication in Hainan province.

Patients and study design
This randomized controlled trial was conducted from June 2022 to February 2023 in the outpatient clinic of the Department of Gastroenterology, Second Affiliated Hospital of Hainan Medical University.Ethics committee approval was obtained for the conduct of the study.The inclusion criteria used were: (1) 13C urea breath test positive confirmed diagnosis of H. pylori infection in patients who are 18-75 years of age;(2) none of these infected patients had any previous history of diseases such as severe liver insufficiency, renal insufficiency, gastrointestinal tumor, and history of PPI, antibiotic, or other drug use within the past 4 weeks; (3) all patients agreed to participate in the study and signed an informed consent form.Exclusion criteria included were (1) history of gastrointestinal tumors or surgery, (2) allergy to any of the drugs used in the study, (3) patients with severe mental disorders that prevented communication, (4) refusal to participate in the study.Ultimately 135 Hp-infected patients were included in the study.
This was a randomized controlled trial in which study participants were numbered in order of visit, 1-135.The treatment regimen that each subject receives is generated from the resulting random allocation sequence generated by an investigator not involved in data collection using Research Randomizer software (http:// www.rando mizer.org) and is placed in a sequential, sealed, opaque envelope.The envelope is opened and the subject receives the appropriate treatment when an eligible subject agrees to enter the trial.Study participants were randomly assigned to the three treatment groups according to a 1:1:1 ratio.During the design of the study, we took into account that the knowledge of the complete treatment regimen by the study subjects might be beneficial to increase the compliance and cooperation of the subjects, which would facilitate the conduct of the study and the recruitment of the subjects.Therefore, subjects were aware of their subgroups and the medications they were taking.In the course of this clinical study, the observation of indicators, the collection of data and the formation of Conclusion VPZ dual therapy and quadruple therapy shows promise of not being worse than the standard quadruple therapy by a clinically relevant margin.More studies might be needed to definitively determine if the new therapy is equally effective or even superior.Keywords Helicobacter pylori, Dual therapy, Quadruple therapy, Vonoprazan; non-inferiority conclusions were carried out without knowledge of the group in which the subjects were placed and without knowledge of the type of measure received.
This clinical trial study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Hainan Medical University (No. LW2023113).The trial was registrated on 17/10/2023 (ChiCTR2300076723).

Sample size calculation
Based on the expert consensus on statistical considerations in the design of non-inferiority clinical trials developed by the China Clinical Trial Statistical Study Group (CCTS) and the guidelines for the design of noninferiority trials developed by the FDA, we developed non-inferiority cut-offs for the trials based on the degree of net benefit of efficacy in the control group.According to previous similar studies, the eradication rate was 98.5% for vonoprazan dual therapy [18], 97.4% for vonoprazan quadruple therapy and 96.7% for conventional PPI [19,20].The study was a non-inferiority study with the non-inferiority value set at 10, 80% certainty (Power is 0.8), and a test level of 0.05 (unilateral), assuming the same sample size for each group.PASS 15.0 was used for sample size calculation.The results showed that at least 19 people/group were needed based on the V1 eradication rate, at least 32 people/group were needed based on the eradication rate in group V2, and at least 40 people/ group were needed based on the eradication rate in group V3.Taking the maximum value from the calculations, a minimum of 40 people were needed in each group, and a total of 120 people were needed in the three groups, and taking into account that there may be a 10% lost visit rate, it was finally decided to include 135 people (Sample size calculation using pass 15).

Treatments and follow-up
135 patients were randomly assigned to one of three different eradication regimens.Group V1: The patients were administered vonoprazan 20 mg twice daily and amoxicillin (AMX) capsules 1.0 g three times daily for 14 days; Group V2: The patients were administered vonoprazan 20 mg, amoxicillin capsules 1.0 g, furazolidone 0.1 g and bismuth potassiulm citrate 240 mg, twice daily for 14 days; Group V3: The patients were administered ilaprazole 5 mg, Amoxicillin 1.0 g, Furazolidone 0.1 g and bismuth potassiulm citrate 240 mg twice daily for a fortnight.Acid suppressants and bismuth were administered half an hour before the meals and antibiotics were given half an hour after the meals [4].After 14 days of continuous administration, medication was discontinued for 1 month and a 13 C urea breath test to determine the eradication status of Hp.Overall considering the interests of the participants, we selected to sue amoxicillin and furazolidone, which have low resistance rates in China.It has been reported that compared to these two antibiotics, CLR and metronidazole have higher resistance.The doses of antibiotics used in the quadruple regimen are those recommended in the national consensus [4].The dosage was increased after considering that there was only one antibiotic included in the dual therapy.The patients were followed up by telephone during and after the medication to determine whether the medication was administered regularly and whether any other adverse reactions developed during the course of administration.

Study outcome
The primary study endpoint was the eradication rate for Hp infection of the three treatment regimens, with secondary study endpoints of safety and economic benefit.A successful eradication was considered to be achieved if the 13 C-UBT showed a DOB < 4.0 after 14 days of regulated dosing and 1 month of drug withdrawal.However, in the per-intent analysis, patients lost to the -up and those who failed to take the medication regularly for 14 days for multiple reasons were considered for the failed eradication in enrolled patients.We considered the treatment options to have an acceptable eradication rate when the eradication rate was > 85%.

Statistical analysis
Categorical variables were expressed as ratios, and differences between groups were analyzed by the Kruskal-Wallis H test and multiple corrections were performed using the Bonferroni test.Continuous variables were expressed as mean (±) standard deviation, and comparisons were made using analysis of variance (ANOVA) under conditions consistent with normality.SPSS 26 was used to complete the above analysis.In addition, non-inferiority was tested using SAS 9.4, with the non-inferiority value set at 10%.Non-inferiority was established if the lower limit of the 95% confidence interval for the difference in eradication rates was > − 10%.

Results
We found that 2 patients were lost to follow-up and 43 eventually completed treatment in Group V1. 2 were lost to follow-up, 2 were discontinued due to various intolerable adverse effects, and 41 eventually completed treatment in Group V2. 2 patients discontinued the therapy due to intolerable adverse effects and 43 eventually completed treatment in Group V3 (depicted in Fig. 1).Table 1 summarizes the demographic clinical characteristics of enrolled patients.There were no statistically significant differences observed in demographic characteristics between the three groups of patients on different treatment regimens.
According to the findings of the multiple non-inferiority test, the lower limit of the 95%CI for the difference in eradication rates between the two groups (V1 vs V2) and the two groups (V3 vs V2) in the ITT analysis was less than the non-inferiority value, and it did not conform to non-inferiority.However, in the PP analysis, the lower limit of the 95% CI for the difference in eradication rates between the two groups and the two groups was greater than the non-inferiority value.That is, according to the actual eradication rates, the eradication efficacy of V1 and V3 was non-inferior to that of V2, which is consistent with the results obtained from the Kruskal-Wallis H Test (Tables 2-3  and an eradication rate of 88.4% (38/43, 95%CI 78.4-98.4%)by PP analysis.There was no significant difference in the Hp eradication rate between the three groups (p > 0.05) (Fig. 2 and Table 3).This study involved three subgroups, and in the multiple hypothesis correction test (Table S1), there was no statistical difference in the findings between these subgroups V1, V2, and V3.
The most common adverse reaction to standard quadruple therapy was abdominal pain (Table 4).The incidence of nausea was markedly higher in group V2 in comparison to the other two treatment regimens (P < 0.05).The incidence of adverse reactions in groups V1, V2 and V3 were 2.3% (1/43), 19.5% (8/41) and 14.0% (6/43) respectively.The incidence of adverse reactions in groups V1 was significantly less in comparison to the other two treatment regimens (p < 0.05).In the multiple hypothesis correction test (Table S2), there was no statistical difference in the nausea between these subgroups   The V3 group incurred the highest medical costs and cost-benefit ratios (Table 5).The V1 and V2 regimen incurred lower medical costs, lower cost-effectiveness ratios as well as higher economic benefits than the V3 regimen.

Disscussion
The success rate of HP eradication regimens involving PPIs is continuously decreasing due to increased antibiotic resistance as well as their insufficient acidsuppressive effect,.Therefore, it is difficult to improve the therapeutic efficacy of PPIs even when their dosage is increased [21].VPZ can effectively control the gastric PH above 4.0 most of the time with a dose of 20 mg twice daily, which can exhibit as strong and a long period acidsuppressing effect [22][23][24].we observed that patients with successful Hp eradication displayed a higher range of fluctuation in 24-hour gastric pH than those with failed eradication, and a higher pH has been reported to be beneficial for Hp eradication [25].Amoxicillin and clarithromycin, which are commonly used in Hp eradication, showed the best antibacterial effect at a pH of 6-7 [26].
As indicated in Table 6, our results are similar to the recent findings of Lifen Lu et al. who reported that VPZ quadruple therapy, whether administered for 10 days or 14 days, can achieve eradication rates higher than 90% and was not inferior to standard PPI quadruple therapy [19].VPZ has been included as an acid-suppressing drug in first-line and second-line Hp eradication regimens and the secondary eradication rate was found to be above 90% in Japan [34].Interestingly, in a study by YI Hu and Wen Gao, the eradication rate of high-dose AMX in combination with VPZ was also observed to be above 85% [27,28], but some studies have shown that the eradication rate of VPZ dual therapy was not satisfactory [7].According to PP analysis, the VPZ dual therapy in this study demonstrated an acceptable eradication effect (eradication rate > 85%).Perhaps enhanced acid suppression and prolonged treatment duration are beneficial in improving the eradication rate of VPZ dual therapy [7 ，30-31].Consider quadruple therapy if dual therapy is controversial.dueto，In studies of VPZ quadruple therapy, Hp eradication rate mostly exceeded 90% [19,29,30].In addition to dual and quadruple therapies, the VPZ triple therapy in foreign studies also seems to have good eradication results, but prolonged treatment time does not show an advantage in triple therapy [33].
In terms of adverse reactions, adverse reactions observed in the VPZ regimen were mainly dizziness and nausea, especially nausea was apparently more frequent in VPZ quadruple therapy, whereas major adverse reaction in standard PPI therapy group was pronounced abdominal pain.Additionally, in previously reported studies on quadruple therapy, although a high eradication rate was achieved, the incidence of adverse reactions was relatively as high as 30% for VPZ quadruple therapy and 27.1% for standard PPI quadruple therapy [29].Moreover, in addition to common GI adverse effects, HP regimens containing VPZ have been reported to cause systemic reactions such as chest pain, generalized pain and dizziness [35].The higher incidence of adverse reactions associated with  VPZ quadruple therapy and standard therapy can significantly affect patients' compliance and quality of life during the treatment, which should be taken into consideration.Therefore, VPZ dual therapy can be a good choice for the treatment of Hp infection.
Our study has some limitations: (1) It was a single-centre randomized controlled trial and the sample size was small, further multi-centre, large sample studies are still needed to validate our results; (2) This study did not differentiate between patients who had been initially eradicated of Hp and those who were re-eradicated of Hp, and HP infections were not cultured in these study participants, lacking data on HP drug resistance.Drug resistance may adversely affect eradication rates and influence study results; (3) participants were not monitored for 24 hours for PH, which may also adversely affect eradication rates.
In conclusion, VPZ dual therapy and quadruple therapy shows promise of not being worse than the standard quadruple therapy by a clinically relevant margin.More studies might be needed to definitively determine if the new therapy is equally effective or even superior.In other aspects, VPZ dual therapy is safer, less economically costly.Wen Gao [28] VPZ 20 mg/40 mg + AMX1.0 g tid (

Fig. 1
Fig. 1 Flow chart of the randomized grouping of patients enrolled in the study

Fig. 2
Fig. 2 Comparison of the Hp eradication rates in three different treatment regimens

Table 1
Demographic characteristics of the patients enrolled in the study

Table 2
Multiple non-inferiority analysis for Hp eradication rates P † p-value for non-inferiority test CI confidence interval, ITT intention-to-treat, PP per-protocol

Table 3
Kruskal-Wallis H Test analysis for Hp eradication rates P p-value for Kruskal-Wallis H TestITT intention-to-treat, PP per-protocol

Table 4
Comparison of major adverse events between the three treatment options

Table 5
Cost-effectiveness ratios